2.1 Pancreatic Cancer
Pancreatic cancer is the second most common visceral malignancy as well as the fifth leading cause of cancer mortality in the United States, accounting for one fifth of all gastrointestinal (GI) cancer deaths. Pancreatic cancer is a disease of the industrialized world. There is a tenfold difference between the highest incidence rate, in American black males (15.2 per 100,000), and the lowest rates, in Hungary, Nigeria, and India (1.5 per 100,000) (Waterhouse et al., 1976, Lyon: International Agency for Research on Cancer, Vol. 3). High risk has also been observed in Polynesian males, including native Hawaiians and New Zealand Maoris. Like many other cancers, pancreatic cancer usually strikes after age 50. The incidence of pancreatic cancer has risen with an increase in the average life span. For example, the incidence in Japan rose from 1.8 per 100,000 in 1960 to 5.2 per 100,000 in 1985 (Beazley et al., 1995, Clinical Oncology, Chapter 15).
Aside from advanced age, smoking is the main risk factor for pancreatic cancer—a smoker is three to four times more likely than a nonsmoker to acquire the disease. People frequently exposed to certain petroleum, chemical and metal products may also be at increased risk. Excessive dietary fat and protein as well as low fiber intake may promote the disease. Diabetes is linked to pancreatic cancer for 10% to 20% of patients diagnosed with pancreatic cancer also have diabetes. Other hereditary diseases associated with pancreatic cancer include inflammatory pancreatic problem, Gardner's syndrome (where growths develop inside and outside the colon), the skin and nerve disease neurofibromatosis, and multiple endocrine neoplasia, a condition that promotes growth of noncancerous islet cell
Pancreatic cancer is difficult to detect early because the pancreas is located deep inside the body and is hidden behind other organs. The retroperitoneal location of the pancreas is considered a major obstacle to early treatment. Further, pancreatic cancer does not usually cause symptoms in its early stages. Even if symptoms do occur, they may be vague and the tumor has already spread outside of the pancreas (metastasis). Signs include abdominal pain, unexpected weight loss, nausea, loss of appetite, weight loss, digestive problems, jaundice, or yellowing of the skin are nonspecific and often overlap with other diseases. The rarer endocrine (or islet cell) cancers may also cause restlessness, loss of energy, irritability, sweating, tremor, drowsiness and severe confusion. Because the symptoms are so general in nature, several diagnostic tools are frequently used, e.g., ultrasound, CT scan, MRI (magnetic resonance imaging), barium meal ERCP (endoscopic retrograde cholangiopancreatography) and PTC (percutaneous transhepatic cholangiopancreatography) tests.
The staging of pancreatic cancer is based on the revised criteria of TNM staging by the American Joint Committee for Cancer (AJCC) published in 1988. Staging is the process of describing the extent to which cancer has spread from the site of its origin. It is used to assess a patient's prognosis and to determine the choice of therapy. The stage of a cancer is determined by the size and location in the body of the primary tumor, and whether it has spread to other areas of the body. Staging involves using the letters T, N and M to assess tumors by the size of the primary tumor (T); the degree to which regional lymph nodes (N) are involved; and the absence or presence of distant metastases (M)—cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Each of these categories is further classified with a number 1 through 4 to give the total stage. Once the T, N and M are determined, a “stage” of I, II, III or IV is assigned. Stage I cancers are small, localized and usually curable. Stage II and III cancers typically are locally advanced and/or have spread to local lymph nodes. Stage IV cancers usually are metastatic (have spread to distant parts of the body) and generally are considered inoperable.
More than 90% of pancreatic malignancies arise from ductal epithelium, even though less than 15% of the pancreas by mass is made up of ductal tissue. At least 90% of pancreatic cancers are exocrine cell cancers called adenocarcinomas, usually originating in the head of the gland. Other tumors arising from the pancreas include acinar cell carcinoma (about 5%), cystadenocarcinoma (mucinous), adenosquamous carcinoma, solid microglandular carcinoma, carcinoid, sarcoma, and malignant lymphoma. Cancers arising in the head of the pancreas must be distinguished from peripancreatic lesions arising from the distal common bile duck, the ampulla of Vater, or the duodenum. While ampullary cancer is the most resectable and associated with the most favorable prognosis, survival rates with all three are higher than with pancreatic cancer.
Surgery is by far the most effective choice of treatment. A Whipple procedure removes the head of the pancreas, part of the small intestine, and some of the tissues around it. Enough of the pancreas is left to continue making digestive juices and insulin. Total pancreatectomy takes out the whole pancreas, part of the small intestine, part of the stomach, the bile duct, the gallbladder, spleen, and most of the lymph nodes in the area. Distal pancreatectomy takes out only the tail of the pancreas. Unfortunately, roughly 80% of individuals on presentation are ineligible for a curative attempt once metastasis to the peritoneal surfaces, the omentum, the liver, and the transverse mesocolon takes place. At that point, surgery is performed to relieve symptoms. For instance, if the cancer is blocking the small intestine and bile builds up in the gallbladder, biliary bypass may be performed by sewing the gallbladder or bile duck directly to the small intestine.
Further, Whipple procedure, although a popular choice of treatment, can cause numerous complications such as sepsis, biliary or pancreatic fistula, and bleeding. The overall morbidity rate varies between 27% and 46%. (Pellegrini et al., 1989, Arch Surg. 124:778–81). Until recently, 5-year survival after pancreaticoduodenectomy for cancer was exceedingly rare. Survival rates of 3% to 25% are currently being reported. Occasionally, long-term survivors are reported with a large tumor, but the majority of the survivors are those who have small lesions and negative lymph nodes (T1, N0, M0). Mean survival after pancreatic resection is 17 months.
The use of biological therapy (using the body's immune system to fight cancer), otherwise known as biological response modifier (BRM) therapy or immunotherapy, is currently being tested for pancreatic cancer. Similarly, adjuvant therapy is gaining popularity by administering to the patient after “successful” Whipple resections, either 5-fluorouracil (5-FU) or radiation therapy (20 Gy). Studies have reported that the median survival for the control groups was 11 months, compared with 20 months for the treatment groups (Kalser et al., 1985, Arch Surg. 120:899–903).
Although initially considered to be radioresistant, pancreatic exocrine tumors are responsive to radiation therapy. Nonetheless, the curative rate is extremely low and the side effects are undesirable. The proximity of radiosensitive tissues, including the liver, kidney, and duodenum, severely limits the efficacy of external-beam radiation therapy and has led to innovative approaches for delivering high-dose treatment, including precision high-dose external-beam techniques, interstitial or brachytherapy, and intraoperative and adjuvant radiation therapy. There is reported value for all these techniques, but because of the heterogeneity of patients, tumor size, stage of disease, performance status, and volume of the tumor, it is difficult to make a definitive conclusion concerning the superiority of one modality over the others. Titanium clips, which do not interfere with CT studies, can be surgically placed to mark the margins of the tumor, thus enabling the radiation therapist to design fields that will maximize tumor dosage and minimize injury to radiosensitive, normal adjacent structures (Dodelbower et al., 1984, World J Surg. 8:919–28).
Many chemotherapeutic drugs have been tried in the past as single agents for the palliation of pancreatic cancer, but the results were generally disappointing. Nevertheless, the role of chemotherapy in the management of pancreatic cancer is continually evolving. Oftentimes, chemotherapy with radiation in adjunct to surgery is used. In general, chemotherapy can achieve long-term survival rates of up to 15% to 20%, even in patients with recurrent or metastatic disease (Ali et al., 2000, Oncology 14(8):1223–30). Unfortunately, the high initial response rates to first line chemotherapy does not appear to translate into a survival benefit (Kohno and Kitahara, 2001, Gan To Kagaku Ryoho 28(4):448–53). Moreover, there are many undesirable side effects associated with chemotherapy such as temporary hair loss, mouth sores, anemia (decreased numbers of red blood cells that may cause fatigue, dizziness, and shortness of breath), leukopenia (decreased numbers of white blood cells that may lower resistance to infection), thrombocytopenia (decreased numbers of platelets that may lead to easy bleeding or bruising), and gastrointestinal symptoms like nausea, vomiting, and diarrhea. Active chemotherapeutic agents include hexamethylmelamine, bleomycin, cisplatin, mitomycin C, doxorubicin, methotrexate and Gemzar (gemcitabine HCL).
The identification of active chemotherapeutic agents against cancers traditionally involved the use of various animal models of cancer. The mouse has been one of the most informative and productive experimental system for studying carcinogenesis (Sills et al., 2001, Toxicol Letters 120:187–198), cancer therapy (Malkinson, 2001, Lung Cancer 32(3):265–279; Hoffman R M., 1999, Invest New Drugs 17(4):343–359), and cancer chemoprevention (Yun, 1999, Annals NY Acad Sci. 889:157–192). Cancer research started with transplanted tumors in animals which provided reproducible and controllable materials for investigation. Pieces of primary animal tumors, cell suspensions made from these tumors, and immortal cell lines established from these tumor cells propagate when transplanted to animals of the same species.
To transplant human cancer to an animal and to prevent its destruction by rejection, the immune system of the animal are compromised. While originally accomplished by irradiation, thymectomy, and application of steroids to eliminate acquired immunity, nude mice that are athymic congenitally have been used as recipients of a variety of human tumors (Rygaard, 1983, in 13th International Cancer Congress Part C, Biology of Cancer (2), pp37–44, Alan R. Liss, Inc., NY; Fergusson and Smith, 1987, Thorax, 42:753–758). While the athymic nude mouse model provides useful models to study a large number of human tumors in vivo, it does not develop spontaneous metastases and are not suitable for all types of tumors. Next, the severe combined immunodeficient (SCID) mice is developed in which the acquired immune system is completely disabled by a genetic mutation. Human lung cancer was first used to demonstrate the successful engraftment of a human cancer in the SCID mouse model (Reddy S., 1987, Cancer Res. 47(9):2456–2460). Subsequently, the SCID mouse model have been shown to allow disseminated metastatic growths for a number of human tumors, particularly hematologic disorders and malignant melanoma (Mueller and Reisfeld, 1991, Cancer Metastasis Rev. 10(3):193–200; Bankert et al., 2001, Trends Immunol. 22:386–393). With the recent advent of transgenic technology, the mouse genome has become the primary mammalian genetic model for the study of cancer (Resor et al., 2001, Human Molec Genet. 10:669–675).
While surgery, chemotherapeutic agents, hormone therapy, and radiation are useful in the treatment of pancreatic cancer, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to cancer therapy and management of the disease by using an oral composition comprising yeasts.
2.2 Yeast-Based Compositions
Yeasts and components thereof have been developed to be used as dietary supplement or pharmaceuticals. However, none of the prior methods uses yeast cells which have been cultured in an electromagnetic field to produce a product that has an anti-cancer effect. The following are some examples of prior uses of yeast cells and components thereof:
U.S. Pat. No. 6,197,295 discloses a selenium-enriched dried yeast product which can be used as dietary supplement. The yeast strain Saccharomyces boulardii sequela PY 31 (ATCC 74366) is cultured in the presence of selenium salts and contains 300 to about 6,000 ppm intracellular selenium. Methods for reducing tumor cell growth by administration of the selenium yeast product in combination with chemotherapeutic agents is also disclosed.
U.S. Pat. No. 6,143,731 discloses a dietary additive containing whole β-glucans derived from yeast, which when administered to animals and humans, provide a source of fiber in the diet, a fecal bulking agent, a source of short chain fatty acids, reduce cholesterol and LDL, and raises HDL levels.
U.S. Pat. No. 5,504,079 discloses a method of stimulating an immune response in a subject utilizing modified yeast glucans which have enhanced immunobiologic activity. The modified glucans are prepared from the cell wall of Saccharomyces yeasts, and can be administered in a variety of routes including, for example, the oral, intravenous, subcutaneous, topical, and intranasal route.
U.S. Pat. No. 4,348,483 discloses a process for preparing a chromium yeast product which has a high intracellular chromium content. The process comprises allowing the yeast cells to absorb chromium under a controlled acidic pH and, thereafter inducing the yeast cells to grow by adding nutrients. The yeast cells are dried and used as a dietary supplement.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.